Anhydro 2-carboxylicacylamino-3, 5-diiodobenzoic acids and process



Patented Mar. 31, 1953 UNITED STATES PATENT OFFICE 2.633.466' ANHYDROZ-CARBOXYLICACYLAMINQ-3,5, DHODOBENZOIC ACIDS AND PROCESS.

--Vernon H. Wallingford, Ferguson, Mo., assign'or to MallinckrodtChemical Works, St. Louis, Mo., a: corporation of Missouri No Drawing.Application December 27, 1948,]

Serial No. 67,570

,15xClaims. (Cl. 2609-244) compounds of related structure; theprovisionof compounds of thetype-referred -to which can be. used toprepare products many of which are characterized by the followingproperties: substantial water-solubility of their salts; low toxicity tohuman beings, stability under normal conditions of storage and use, andvalue as contrast media for X-ray diagnosis; and the provision-ofmethods for-preparing compounds of the type referred to. Other objectswill be in part apparent and in part pointed out'hereinafter.

The invention accordingly comprises the ingredients and combinations ofingredients, the proportions thereof, stepsand sequence of steps, andfeatures of composition and manipulation, which will be exemplified inthe products and methods hereinafter described, and thescope of theapplication of which will be indicated in the followin claims.

The compounds of my invention are new polyiodi-natedanhydro-2-acylaminobenzoic acids, conforming to the general formula:

in which R. is an aryl or aralkyl radical, a-nucleariodine-containingderivative of such a radical, or an alkyl radical.

These new compounds can be prepared conveniently by reacting a2-acylamino-3,5-diiodobenzoic acid or 2-amino-3,5-diiodobenzoicacid withan acid anhydride-or-acid chloride. The product crystallizes well and istherefore easily recovered and purified in contrast 'to the'2-acyl-..amino-3,5-diiodobenzoic acids which crystallize with 'difiicultyand'consequently are diflicult to recover and purify byconventionalmethods.

In my copending application, Serial No. 40,000, filed July 21, 1948,I'have shown that certain 2+acylamino-3;5-diiodobenzoic acids are'valuable new contrast"media for Xray dagnosis.

Because they are customarily administered *by intravenous injection of-asolution ofone of their salts, these compounds must be of exceptionalpurity. The anhydro compounds of the present invention provide a simple.and effective method of preparing these exceptionally-pure acids andtheir salts.

compound can then be converted'b'ack to the free acid if desired. It" isnot however, necessary to again isolate the free acid, for the anhydrocompound can be dissolved in a solution of some physiologically suitablebase, such. as,

for example, sodium hydroxide, wherebya-salt,

of the acid is. formed which is suitable'for .injece 014 From theanhydro compounds of my inven.-!

tion, other valuable compounds can be prepared.- For example they may bereacted with certain; amino acids to give 2 -acylamino-3-,5 -diiodo--.vbenzoyl amino acids, which are useful X-ray.

contrast media.

The following examples illustrate the inven-.-

tion:

EXAMPLE 1 2-'a.cetylamino-3,5-diidobenz0ic. acid.

2-amino-3.5-diiodobenzoic acid (9.7 grams) was mixed with benzol ml.) ina flask provided" witha short air condenser, then acetyl chloride (4ml.) was added-and the'mixture heated for two hours on a steam-bath.There was'some evolutionof hydrogen chloride, but acetylation wasevidently incomplete, so dioxane-(35 ml.)

was added along with additional acetyl-ch10 ride (4 ml.). Afterone houron the steam bath all'solids were dissolvedandinanother hour all"wasacidified with hydrochloric acid to give 8.1. grams of2-acetylamino-3,5,-diiodobenzoic abid.

melting at 224226 C- Acetylation under these conditions gives a yield ofabout of the regular acetyl compound,andz.20% lof theanhydro form.

Thus, to purify-a --2-acyl-amino'-3,5- dioodobenzoic acid, itisconverted; to the-corre sponding anhydro derivative and the latter ispurified by recrystallzation. The-pure'anhydro 3 EXAMPLE 2Anhydro-Z-acetyZamino-3,5-diiodobenzoic acid 2-amino-3,5-diiodobenzoicacid (57.8 grams) was mixed with acetic anhydride (260 ml.) containing 3drops of concentrated sulfuric acid. The mixture was refluxed until allof the solid was in solution and then for an additional 15 minutes. Aslight amount of impurities, in the form of a fiocculent grayprecipitate, did not dissolve. Large crystals of anhydro-Z-acetylamino-3,5-diiodobenzoic acid separated on cooling. These were collected on afilter and washed with acetic anhydride, in which they are only veryslightly soluble. The flocculent gray precipitate collected in a layernext to the filter paper and could be separated from the productmechanical- 1y. Most of the color remained in the mother liquor. Theproduct, when dried, weighed 58.5 grams (95% yield) and melted at196-197.5 C. The product (19 grams) obtained by recrystallizing 23 gramsfrom acetic acid (250 ml.) did not melt sharply but over a range from197 to 214 C. Recrystallized again, this time from acetic anhydride, theproduct (17.6 grams) softened at 196 and melted at 199-201 C. It isprobable that recrystallization from acetic acid resulted in partialopening of the ring. Found on analysis: 26.35, 26.06%, carbon; 1.5%,1.53% hydrogen. Calculated for C9H5O2NI2: 262% carbon, 1.2% hydrogen.

EXAMPLE 3 2-acetyZamino-3,5-diiodobenzoic acid Anhydro 2 acetylamino 3,5diiodobenzoic acid grams) was stirred with dioxane (25 ml.) and water(50 ml.) at room temperature and sodium hydroxide solution (35 Baum) wasadded a few drops at a time to keep the mixture definitely red tophenolphthalein. A total of 3 ml. of sodium hydroxide was added over aperiod of two hours, by which time al1 of the solid had dissolved. Thesolution was diluted to 200 ml. with water and made acid to litmus withacetic acid. No precipitate formed, indicating the absence of anyunacetylated acid. The mixture was then made acid to Congo red usingconcentrated hydrochloric acid and the solid was collected on a filter,washed and dried at 105 C. It weighed 9.0 grams and melted at 229.5-230C. From the mother liquor, 0.9 gram separated as silky crystals, meltingat 230-231 C. The melting point of the purified2-acetylamino-3,5-diiodobenzoic acid varies somewhat with the rate ofheating and the temperature at which the specimen is put into themelting point apparatus. This sample was carefully rechecked by placingit in the apparatus at 210 C. and increasing the temperature at the rateof 3 C. per minute. It melted to a red liquid at 2285-230 C. Theequivalent weight was found to be 430 (theory is 430.8). Found onanalysis: 25.14, 24.73% carbon; 1.81, 1.79% hydrogen. Calculated forC9H'1O3NI2: 25.1% carbon; 1.62%

hydrogen.

- EXAMPLE 4 Anhydro-Z-batyrylamino-3,5-diiodobenzoic acid 'A mixture of2-amino-3,5-diiodobenzoic acid (9.7 grams), n-butyric anhydride (25 ml.)and one drop of concentrated sulfuric acid was refiuxed in a 200-cc.round-bottom flask. The solid did not dissolve readily, but solution wasimmediate when dioxane (25 ml.) was added.

4 After refluxing for one-half hour and cooling, an abundant qnantity ofcrystals formed. After standing overnight, the crystals were collectedon a filter, washed with two 10-ml. portions of acetic anhydride anddried at 105 C. The anhydro-2-butyrylamino-3,5-diiodobenzoic acidproduct weighed 7.5 grams (68% of theory) and melted at 153-154 C. Theyield could have been improved by hydrolzing the mother liquor, for aconsiderable amount of solid separated when water was added. Found onanalysis: 29.81, 30.28% carbon; 2.01, 2.36% hydrogen. Calculated forCuHcOzNIzZ 29.94% carbon, 2.06% hydrogen.

EXAMPLE 5 2-butyrylamino-3,5-diiodobeneoic acid A mixture of theanhydro-form of Z-butyryl- ..amino-3,5-diiodobenzoic acid (2 grams),water (50 ml.) and dioxane (50 ml.) was warmed to (SO-75 C. on the steambath. It was stirred and kept alkaline to phenolphthalein paper withsodium hydroxide. The resulting solution was treated with activatedcarbon, filtered and diluted to about 250 ml. with water. The additionof acetic acid (1:5) produced a white fiocculent gelatinous precipitatewhich was collected on a filter, Washed, and dried overnight at C. Thepurified 2-butyrylamino-3,5-diiodobenzoic acid weighed 1.7 grams (85% oftheory) and melted at 2035-205 C. Analysis showed; 28.87, 28.59% carbon;2.37, 2.33% hydrogen. Calculated for C11H11O3NI22 28.76% carbon; 2.42%hydrogen.

EXAMPLE 6 2- (n-caproylamino) -3,5-diiodobenzoic acid2-amino-3,5-diiodobenzoic acid (9.7 grams) was mixed with dioxane (50ml.) n-caproyl chloride (8 grams-8.4 ml.) and refluxed for two hours.Evolution of hydrogen chloride ceased after one and one-half hours. Themixture was then poured into water (50 ml.), warmed to 70-80 C. andsodium hydroxide was added to maintain the alkalinity of the mixture tophenolphthalein. All of the solid dissolved within 12 minutes. Thesolution was diluted with water ml.), treated with activated carbon,filtered and divided between two 3-liter beakers (which were then filledwith water. These solutions were heated to 65-70 C. and precipitatedfirst with dilute acetic acid and then with dilute hydrochloric acid toa pH of about 4, filtered while still hot and washed. TheZ-(n-caproylamino) 3,5-diiodobenzoic acid product weighed 11.1 gramsafter having been dried at 70 C. overnight. The melting point was 205.5to 2065" C. when the sample was placed in the melting point apparatus atC. and heated at the rate of 4 C. per minute. Analysis showed: 32.3%,32.59% carbon; 3.19, 3.51% hydrogen. Calculated for C13H1503NI2: 32.0%carbon; 3.08% hydrogen.

EXAMPLE 7 Anhydro-Z- (n-caproylamino) -3,5-diz'odobenzoic acid crystalsformed, thus indicating that the caproyl aces-gees;

grams (theory 8.69 grams) and melted at .68-70 C. when air-dried. Thiswas recrystallized from alcohol (90 ml.) to yield-4.9 grams melting at7171.5 C. Found on analysis: 33.2, 33.29% carbon; 2.80, 2.97% hydrogen.Calculated for 33.2% carbon; 2.77% hydrogen.

The anhydro-compound was readily hydrolyzed by digesting '2 grams indioxane (25 ml.) and water (25 ml.) at 70-80" C. andadding sodiumhydroxide solution drop by drop to maintain the pH at 9-11. After18-20'minutes the mixturewas poured into Water (200 ml.) andprecipitated by very dilute acetic acid at60 C. '-The 2-(n-caproylamino)3,'5 diiodobenzoic acid product weighed 2.0 grams and meltedat 213-214C. The equivalent weight was found to be 474 compared to the theory of487. It is probable that slight hydrolysis of the caproyl group occurredduring this operation.

EXAMPLE 8 2-benzoyZamino-3,5-diiodobenzoic acid A mixture of2amino-3,5-diiodobenzoic acid (9.7 grams), dioxane (50 m1.) and benzoylchloride (6.8 ml.) was placed in a 200 cc. round-bottom flask providedwith a reflux condenser. After refluxing for 3 /2 hours, the reactionmixture was .cooled,;poured into water (50 ml.) ,warmed to 70-80 C.anddissolved by adding 35 Baum sodium hydroxide solution ml.) in smallquantities, keeping the solution just alkaline to phenolphthalein. Thesolution was then diluted with water (150 ml.), treated with activatedcarbon, filtered and divided between two 3-liter beakers filled withwater. After making the solution acid to litmus, it ,wasallowed to standovernight. On thefollowing. morning both beakers were filled with afluffy gelatinous precipitate. The pH was adjusted to 4 usingbromocresol green paper. The precipitate was removed by filtration and asecond crop was obtained from the mother liquor after first making itacid to Congo red with dilute hydrochloric acid. After drying overnight,the first crop weighed 8.1 grams and the second crop weighed 3 grams.The total yield of 2-benzoylamino-3,5-diiodobenzoic acid was 90% oftheory. The melting point was 196 to 198 C. After recrystallizing fromglacial acetic acid twice and treating with activated carbon each time,the melting point was 211.5 to 213 C. Analysis showed: 34.04, 34.13%carbon; 2.03, 2.05% hydrogen. Calculated for C14H903NI2 34.08% carbon;1.8% hydrogen.

EXAMPLE 9 Anhydro-zebenzoylammo-rafi diiodobenzozc acid A mixture of2-benzoylamino-3,5 diiodobenzoic acid (10.grams) and acetic anhydride(50 ml.) was refluxed for 1 /2 hours, but much solid remainedundissolved. Dissolution was aidedby two 50 ml. portions of dioxane andrefluxing was continued for an additional twenty minutes. On cooling, alarge quantity of needle-shaped crystals formed. When crystallizationappeared to "be complete, the flask 'was'cooled in tapwater whereupon'an additionaL flocculent precipitate was-formed.This-.lattergprecipitate.was .dis

solved by rewarming the-flask and the original needle-shaped crystalswere collected on a filter. They were washed-in a small quantity ofacetic anhydride and dried overnight at C.

The first crop'weighed 6.7 grams and melted at. 228-'-229- C. The secondcrop,-weighed1.3,grams;

and; melted :atw224-225=C. .A mixture'of the two: melted at227-228" 0.,indicatingthemtobe: the ;.same.substanc e. rBy mixed-melting points,

35.21% carloon; 1.17.3, 1.69%;hydrogen. Calcu-- latedforCnHaoaNI-zz35.38%...carbon; 1.49%..hydrogen.

EXAM MIPLE-lQ A mixture of 2-amino-3,5-diiodobenzoic acid (9.7 grams),o-iodobenzoyl chloride (15.8 grams) and dioxane (50 ml.) was refluxedfor four hours. The mixture was cooled, poured into water (50 ml.),warmed to 65 C. and dissolved by keeping the solution alkaline tophenolphthalein with sodium hydroxide. About one-half hour was required,The. solution was diluted with water ml.) and the pH adjusted to 5 with1:5 acetic acid. Theprecipitate was separated by-flltration and. dried.The 2-(o-iodobenzoylamino) -3,5- diiodobenzoic acid weighed 14i5'grams,94% of theory, and melted at 22215 to 224;5 C. with decomposition.Analysis showed: 26.76, 26.80%, carbon; 1.76, 1.75% hydrogen. Calculatedfor C14HsQsNI3 27.15% carbon; 1,30% hydrogen.

The filtrate wasadjusted to pH 2 with dilute hydrochloric acid,whereupon another precipitate, white and fiocculent, formed. Whenfiltered, washed and dried, this weighed 8.3 grams and melted at 158-161C. A mixture of this product with o-iodobenzoic acid melted at 160.5-162 CL, proving them to bethesame substance.

EXAIVIPLE 11 Anhydro-Z- o-z'odobenzoylamino) -3, 5-'diiodobenzoic acid Amixture of 2-(o-iodobenzoylamino)e3,5-diiodobenzoicacid (5 grams) andacetic anhydride (15 ml.) was refluxed for 1 hours. Durin the course ofthe reaction it became apparent. that all of the solid would notdissolve, so 10 ml. and later 3 ml. more of acetic anhydride was added.On cooling, very small crystals separated rapidly. These were collectedon a filter, washed with acetic anhydride and dried at 90 C. The anhydro2 (o-iodobenzcylamino) -3,5-diiodobenzoic acid product weighed 4.2 grams(86% of theory) and melted to a clear, light yellow liquid at. 171-172C. Found on analysis: 28.11, 27.76%

carbon 1.20, 1.10% hydrogen. Calculated for.

C14HsO2NI3: 27.96% carbon; 1.01% hydrogen.

EXAMPLE'lz 2-(a-phenylbutyrylamino) -3,5-dz'iodobenzoic; acid his insmall quantities, keeping the mixture alkaline to phenolphthalein.Solution required about 45 minutes. When the solid was nearly dissolved,an oil separated, but this also dissolved. A total of 8.5 ml. of sodiumhydroxide solution (35 Baum-) was required. The solution was dilutedwith water (150 ml.) treated with activated carbon, filtered, diluted to1800 ml. and precipi- EXANIPLE 13 Anhydro Z-(a-phenyZbutyTyZaminO)-3,5-diiodobenzoic acid A mixture of 2-(a-phenylbutyrylamino) -3,5-diiodobenzoic acid v(2.? grams) and acetic anhydride (20 ml.) wasrefluxed) When it appeared that the solid was not going to dissolve,dioxane (10 ml.) was added and refluxing continued for one-half hourafter solution was complete. N crystals formed when the solution wasallowed to stand overnight. The solution was therefore placed in anevaporating dish and allowed to evaporate spontaneously. In this mannercrystals in the form of needles were deposited in the bottom of thedish, whereas discolored material separated on the sides. Theanhydro-2-(c-phenylbutyrylamino)-3,5-diiodobenzoic acid needles weighed0.8 gram and melted at 113-115.5 C. The disclosed material weighed 1.?grams. The total yield of 2.5 grams was 96% of theory. Found onanalysis: 39.02, 39.42% carbon; 2.43, 2.50% hydrogen. Calculated forC17H13O2NI22 39.i6% carbon, 2.53% hydrogen.

As indicated above, where the poly-iodo compound contains an aryl groupother than the phenyl nucleus of the benzoic acid, additional iodine maybe substituted in this nucleus as well.

Many variations of my invention will be apparent to those skilled in theart. For example, although I prefer an excess of the acid anhydride oracid chloride or dioxane as a solvent, other common solvents can beemployed providing they are inert to the reactants and reaction product.Likewise, although I usually prefer to add a small amount of sulfuricacid as a catalyst to improve the yield and purity of the product, suchaddition is by no means essential.

Throughout the claims it will be understood that the term acyl refers tocarboxylic acyl radicals.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantages results attained.

As many changes could be made in the above methods and products withoutdeparting from the scope of the invention, it is intended that allmatter contained in the above description shall be interpreted asillustrative and not in a limiting sense.

I claim:

1. The method of making an anhydro 2-car- 8.boxylica'cyl'amino-3,5-diiodobenzoic acid which comprises heating a2-carboxylicacylamino-3,5- diiodobenzoic acid with the anhydride of alower aliphatic acid.

2. A compound selected from the group consisting of:

0 LR I N in which R is a radical selected from the group consisting ofmonocyclic hydrocarbon aryl and monocyclic hydrocarbon aralkyl radicals,nu-' clear-iodine-containing monocyclic hydrocarbon aryl and monocyclichydrocarbon aralkyl radicals, and lower alkyl radicals.

3. Anhydro-2-acetylamino 3.5 diicdobenzoic acid, having the structuralformula:

0 (E-CH: I N

4. Anhydro-2-butyrylamino-3,5 diiodobenzoic acid, having the structuralformula: ii

--C:Hl I N 5. Anhydro 2 (n-caproylamino)-3,5-dilodobenzoic acid, havingthe structural formula:

f3 I o 6-C5Hu '6. Anhydro-2-benzoylamino-3,5 diiodobenzoic acid,havingthe structural formula:

7. Anhydro-2-(o-iodobenzoylamino) 3,5 diiodobenzoic acid, having thestructural formula:

f3 I o N I I 8. The method of making an anhydro-2-car-.-

bqxylicacylaminobenzoic acid which comprises heating a compound selectedfrom the group consisting of 2-amino-3,5diiodobenzoic acid and2-carboxylicacylamino-3,5 diiodobenzoic acids with a compound selectedfrom the group consisting of the anhydrides and chlorides of.

chlorides of monocyclic hydrocarbon aromatic,

9 and mixed aliphatic-monocyclic hydrocarbon aromatic acids, and loweraliphatic acids.

9. A compound of the type:

I C-Alkyl in which alkyl represents a lower alkyl group.

10. A compound of the type:

(B-Aryl I N 10 comprises heating a compound selected from the groupconsisting of 2-amino-3,5-diiodobenzoic acid and2-carboxylicacylaminobenzoic acids with a chloride of a lower aliphaticacid.

14. The method of making ananhydro-2-carboxylicacylamino-3,5-diiodobenzoic acid which comprisesheating a compound selected from the group consisting of2-amino-3,5-diiodobenzoic acid and2-carboxylicacylamino-3,5-diiodobenzoic acids with the anhydride of alower aliphatic acid.

15. The method of making anhydro-2-acetylamino-3,5-diiodobenzoic acidwhich comprises heating 2-amino-3,5-diiodobenzoic acid with aceticanhydride.

VERNON H. WALLINGFORD.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 1,951,807 Preiswerk et a1. Mar.20, 1934 2,219,009 Eckert et a1 Oct. 22, 1940 2,458,526 Oberright Jan.11, 1949 2,476,559 Nawiasky July 19, 1949 OTHER REFERENCES Villiger:Chem. Abs., vol. 4 (1910), page 181.

Heller: Chem. Abs., vol. 23 (1928), page 828.

Lothrop et al.: Chem. Abs., vol. 37 (1943), page 2364.

Hirwe et al.: Chem. Abs., vol. 37 (1943), page 4061.

2. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: